An inverse correlation between cancer mortality rates and regional solar UV-B radiation exposure, a major source of vitamin D, has been found for cancers of the breast, colon, rectum, ovary;prostate, stomach, bladder, esophagus, kidney, lung, pancreas, and uterus, as well as non-Hodgkins lymphoma, and multiple myeloma. The anticancer effect of vitamin D is strongly supported by in vitro, animal, and epidemiological studies. Although a large body of evidence now links low vitamin D intake and low serum 25- hydroxyvitamin D (25OHD) to increased risk of various types of cancer, no reports were found of the effects of vitamin D status on all-cancer incidence. Furthermore, no randomized clinical trials have been reported that used a vitamin D intervention sufficient to raise serum 25OHD to optimum levels and that targeted a cancer outcome. A recent population-based study done by our group to determine the anti-fracture efficacy of calcium and vitamin D3 supplementation in healthy postmenopausal women demonstrated that vitamin D3 reduces all-cancer incidence. These findings need to be confirmed with a randomized controlled clinical trial designed with incidence of cancer as the primary outcome variable. In this application we propose to test whether increasing serum 25OHD to optimal levels, while maintaining adequate calcium intake, reduces the incidence of cancer in a population-based sample of postmenopausal women 60+ years of age. The Specific Aims are to: 1. Sample randomly the population of healthy independently-living postmenopausal women 60 years and older from 9 adjacent rural counties in Nebraska;2. Enroll 2300 women into an intervention study, assign them randomly to 1 of 2 treatment groups: 1) vitamin D3 (2000 ID/d) and calcium (1200 mg/d), or 2) vitamin D3 placebo and calcium placebo, and to follow each subject for 4 years;3. Collect and store white blood cells from every subject to test for genetic markers should the intervention be found effective in decreasing the incidence of cancer;4. Determine the effect of supplementation with vitamin D3on incidence of all types of cancer combined;5. Determine in a nested-case control study the association of serum 25OHD collected at randomization and at the end of year 1 of study with risk of cancer over 4 years. At each semiannual visit, the following will be assessed: medical and social history;adverse events;cancer diagnoses;and adherence to supplement/placebo. Annually, we will obtain height and weight and analyze serum 25OHD and1,25-dihydroxyvitamin D. At baseline and end of follow-up, we will assess dietary intake and physical activity. The proposed study addresses the goal of NCI's Strategic Plan to "eliminate the suffering and death due to cancer by 2015." It specifically addresses Strategic Objective 2, to "accelerate progress in cancer prevention." Positive findings from our proposed nutritional intervention study will result in an inexpensive, safe method of preventing cancer.